Beyond Second-Line Therapy in Gastric Cancer


Daniel Catenacci, MD, discusses treatment options after second-line therapy, highlighting options for patients who are PD-L1 positive.

Daniel Catenacci, MD: After second-line therapy, we would follow similar principles in terms of when to switch from second to third line, even more so now there’s an even larger drop-off in clinical trials and databases in terms of what percentage of patients get to third-line therapy, where it’s less than 30% of patients. Going to fourth-line therapy, probably 10% or less will get to that point, and maybe 1% of our patients, those extreme outliers, will get to fifth line or higher.

What do we decide, and what are we doing at the time in third line after these patients that we’ve discussed, these 2 hypothetical patients who have received pembrolizumab, if they’re MSI [microsatellite instability]-high, and then started a general tract therapy of FOLFOX [folinic acid, fluorouracil and oxaliplatin] with paclitaxel, ramucirumab? Or in the HER2-positive setting of a patient who had FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab, then paclitaxel with ramucirumab. Now they’re progressing on their respective therapies, what would we do in the third line?

There are a number of standard approaches. The first and classic one would be to use whichever chemotherapy was remaining of the taxane or irinotecan, whichever one had not been used yet. Typically platinum in first line; 1 of the 2, irinotecan or taxane in the second line; and then the reverse in third line. That has always been a benchmark option there. The response rate there is not very good. It has a lot of room for improvement, but it’s a benchmark to compare to, and it’s about a response rate of 10%.

We also know that trifluridine, tipiracil, or Lonsurf, is an option based on the TAGS phase 3 study, which randomized patients in the third-line setting or higher, a global study, and showed a survival benefit with that agent. So that’s a known option as well in third line or fourth line if you were sequencing all of the regimens we just mentioned.

And then finally, based on the KEYNOTE-59 study, we know that pembrolizumab is an option for patients who have a combined positivity score [CPS] of PD-L1 of 1 or higher. That has been shown to be an incidence of around 60% of patients will have that score. And there’s certainly a known benefit to enriching with PD-L1–positive tumors. The response rates of PD-L1–positive tumors with that cutoff is around 13% for microsatellite stable tumors in the third-line setting or higher. It’s less than 5% for PD-L1–negative patients, and therefore it was not approved.

We also recognize that the higher the level of PD-L1, the better, and the more likely a patient will respond to immunotherapy checkpoint inhibitors that are monotherapy, especially. We have some choices in the third line that would be considered standard.

I would choose one of those chemotherapy versions for the most part, certainly for PD-L–negative tumors. But for PD-L1–positive tumors, we have the added option of pembrolizumab. And if they haven’t had immunotherapy earlier in their sequence course, then it could be considered here.

The reason why is because although the current standards are as I just mentioned, FOLFOX [folinic acid, fluorouracil and oxaliplatin] with trastuzumab for HER2-positive tumors in first line, or FOLFOX [folinic acid, fluorouracil and oxaliplatin] for HER2-negative tumors, there’s been a lot of activity in the first-line setting of this disease with a number of phase 3 studies evaluating FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy plus a targeted agent. The CHECKMATE 649 study, which I had mentioned earlier, was FOLFOX [folinic acid, fluorouracil and oxaliplatin] plus nivolumab versus FOLFOX [folinic acid, fluorouracil and oxaliplatin] alone, an open-label study, a phase 3 study that the primary end point was for patients with a PD-L1 score of 5 or higher. That study showed a clear survival benefit and progression-free survival on response rate improvement, with toxicity. Grade 3/4 toxicity increased around 15%.

We expect this will become our new standard option in the first-line setting for a CPS of 5 or higher for all gastroesophageal adenocarcinomas. That’s a matter of time, and at the time of doing this presentation that has not occurred. But within the next several months, we do expect that to happen. Patients who have already received it in first line would not be indicated to continue it into later lines of therapy, say a third line where it had been previously been approved, except for those patients who have a PD-L1 score of 1 to 5, where typically they won’t be eligible in the first line, at least that’s anticipated. So in the third-line setting, after failing FOLFOX [folinic acid, fluorouracil and oxaliplatin] chemotherapy, then chemotherapy plus ramucirumab in the third-line or higher setting with a PD-L1 score of 1 to 5, one could consider doing that at that point, especially if the patient doesn’t have a heavy burden of disease, a maintained performance status, and not heavy symptoms because immunotherapy won’t work there no matter the PD-L1 score, especially if it’s really low level.

Transcript edited for clarity.

Case: A 71-Year-Old Man With HER2+ Gastric Cancer

Initial Presentation

  • A 71-year-old man complained of a 3-month history of abdominal pain and bloating, a sensation of fullness
  • PMH: HTN, medically controlled; colonoscopy at age 53 was unremarkable; no family history of cancer
  • PE: patient appeared tired, abdominal distention; otherwise unremarkable

Clinical Workup

  • Labs: Hb 9.7 g/dL, plt 111 x 109/L; other lab values WNL
  • Upper endoscopy with biopsy: showed an ulcerative lesion 5.8 cm mass in the cardia of the stomach; biopsy confirmed gastric adenocarcinoma
  • CT of chest/abdomen/pelvis confirmed a 5.8 cm lesion with indistinct margins in the cardia of the stomach; 2 suspicious hepatic lesions
  • EUS: gastric cancer lesion confirmed invasion of the muscularis propria
  • Mutational testing: MSI high, PD-L1 0%, HER2 3+ by IHC
  • Stage IV gastric adenocarcinoma; ECOG 2


  • He was started on XELOX/CAPOX + trastuzumab
    • Dose reduced due to grade 2 diarrhea; unable to control after 4 cycles; discontinued treatment
  • Treatment initiated with a pembrolizumab
    • After 24-months of treatment without progression of disease pembrolizumab was discontinued
  • The patient was started on trastuzumab deruxtecan; repeat HER2 expression testing was not indicated
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